title: Genetic deletion and pharmacological inhibition of phosphodiesterase 10A protects mice from diet-induced obesity and insulin resistance.
abstract: Phosphodiesterase 10A (PDE10A) is a novel therapeutic target for the treatment of schizophrenia. Here we report a novel role of PDE10A in the regulation of caloric intake and energy homeostasis. PDE10A-deficient mice are resistant to diet-induced obesity (DIO) and associated metabolic disturbances. Inhibition of weight gain is due to hypophagia after mice are fed a highly palatable diet rich in fats and sugar but not a standard diet. PDE10A deficiency produces a decrease in caloric intake without affecting meal frequency, daytime versus nighttime feeding behavior, or locomotor activity. We tested THPP-6, a small molecule PDE10A inhibitor, in DIO mice. THPP-6 treatment resulted in decreased food intake, body weight loss, and reduced adiposity at doses that produced antipsychotic efficacy in behavioral models. We show that PDE10A inhibition increased whole-body energy expenditure in DIO mice fed a Western-style diet, achieving weight loss and reducing adiposity beyond the extent seen with food restriction alone. Therefore, chronic THPP-6 treatment conferred improved insulin sensitivity and reversed hyperinsulinemia. These data demonstrate that PDE10A inhibition represents a novel antipsychotic target that may have additional metabolic benefits over current medications for schizophrenia by suppressing food intake, alleviating weight gain, and reducing the risk for the development of diabetes.
authors.affiliation: In Vivo Pharmacology, Merck Research Laboratories, Rahway, NJ.
authors.forename: Andrea R
authors.initials: AR
authors.lastname: Nawrocki
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Rodriguez
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Toolan
authors.forename: Olga
authors.initials: O
authors.lastname: Price
authors.forename: Melanie
authors.initials: M
authors.lastname: Henry
authors.forename: Gail
authors.initials: G
authors.lastname: Forrest
authors.forename: Daphne
authors.initials: D
authors.lastname: Szeto
authors.forename: Carol Ann
authors.initials: CA
authors.lastname: Keohane
authors.forename: Yie
authors.initials: Y
authors.lastname: Pan
authors.forename: Karen M
authors.initials: KM
authors.lastname: Smith
authors.forename: Izzat T
authors.initials: IT
authors.lastname: Raheem
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Cox
authors.forename: Joyce
authors.initials: J
authors.lastname: Hwa
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.forename: Sean M
authors.initials: SM
authors.lastname: Smith
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000235:genetics*; D004032:Diet; D004435:Eating / Q000187:drug effects / Q000235:genetics; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009765:Obesity / Q000188:drug therapy / Q000235:genetics / Q000517:prevention & control*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D010727:Phosphoric Diester Hydrolases / Q000235:genetics* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C586488:2-(6-chloropyridin-3-yl)-4-(1-methoxypropan-2-yl)oxy-N-(6-methylpyridin-3-yl)-7,8-dihydropyrido(4,3-d)pyrimidine-6(5H)-carboxamide; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; C492284:Pde10a protein, mouse; D010727:Phosphoric Diester Hydrolases